Cocaine dependence has been linked closely to deficits in the dopamine (DA) brain system. Chronic cocaine users show impairments in cognitive processes known to be associated with DA (e.g., decision-making, behavioral inhibition, attentional bias). These cognitive impairments have been shown to predict higher drop-out rates, less efficacious therapy, and greater likelihood of relapse. Treatment medications aimed at bolstering cognitive functions via DA modulation might decrease drop-out and enhance clinical outcome. This project will examine the efficacy of DA enhancement therapy that targets cocaine use and cognitive deficits by combining two dopaminergic medications: levodopa and ropinirole. By enhancing presynaptic dopamine release (levodopa) and post-synaptic D2 receptor function (ropinirole), the combined regimen is expected to jointly target dopamine deficits associated with chronic cocaine use and cognitive functions. This dual-target approach is supported empirically by data showing the single medications to be safe and promising for cocaine treatment. Further, combination DA therapy has translated into broad efficacy for the treatment of Parkinson's disease and other neuropsychiatric conditions resulting from DA depletion. The proposed randomized, double-blind, double-dummy controlled clinical trial will compare the combination of levodopa/carbidopa plus ropinirole with levodopa/carbidopa only and placebo. Two-hundred treatment-seeking cocaine-dependent patients will receive 12 weeks of study medication along with evidence-based cognitive-behavioral therapy. It is hypothesized that the combination of levodopa/carbidopa plus ropinirole will improve treatment outcome (cocaine use, retention) and that a dose-response relationship will be supported: [levodopa/carbidopa + 4 mg/d ropinirole] >[levodopa/carbidopa + 2 mg/d ropinirole] >[levodopa/carbidopa + placebo] >[placebo + placebo]. Further, it is hypothesized that the effect of treatment (levodopa/carbidopa + ropinirole) on outcome (cocaine use, retention) will occur indirectly via improved performance on observed behavioral/cognitive measures of decision-making, behavioral inhibition, reward motivation, and attentional bias. The significance of this project lies in its potential to improve cocaine treatment success by combining medications that act simultaneously on dopamine. This project is innovative in testing a new pharmacological remediation approach and in identifying cognitive mechanisms by which DA medications may operate to change cocaine use, providing a potential neurobehavioral marker or proxy for severity of cocaine-related deficits and treatment-related improvement. The Co-Principal Investigators (Schmitz and Lane) have complementary and integrated expertise in clinical trial research, laboratory behavioral measurement, and psychopharmacology. The scientific environment of the UT-Houston Center for Neurobehavioral Research on Addictions (CNRA) will contribute to the success of the project. PUBLIC HEALTH RELEVANCE: Most cocaine dependent patients suffer from deficits in cognitive function that, if left untreated, predict poor outcome. The present study investigates a pharmacotherapeutic intervention designed to improve cocaine treatment success by combining medications that act simultaneously on dopamine, the brain system that is critically associated with chronic cocaine use and cognitive functions. Treatment with levodopa/carbidopa plus ropinirole (tested at two doses) will be compared to levodopa/carbidopa alone, and placebo. Measurement of performance on behavioral/cognitive measures of decision-making, behavioral inhibition, reward motivation, and attentional bias will be conducted at treatment entry and at repeated time points during the 12-week treatment. It is hypothesized that treatment with levodopa/carbidopa + ropinirole will produce superior outcomes in terms of reduced cocaine use and increased treatment retention and that these effects will occur indirectly via improved performance on observed cognitive mechanisms. There is a significant public health need to improve the outcome of treatments for cocaine dependence. This project responds to the current RFA-DA-10-006 by evaluating a pharmacotherapeutic intervention that may jointly improve cognitive functioning and attenuate drug use.